Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target.

PURPOSE OF REVIEW: Obesity has increased worldwide recently and represents a major global health challenge. This review focuses on the obesity-associated cellular senescence in various organs and the role of these senescent cells (SnCs) in driving complications associated with obesity. Also, the ability to target SnCs pharmacologically with drugs termed senotherapeutics as a therapy for these complications is discussed. RECENT FINDINGS: Several studies have shown a positive correlation between obesity and SnC burden in organs such as adipose tissue, liver, and pancreatic-ß-cells. These SnCs produce several secretory factors which affect other cells and tissues in a paracrine manner resulting in organ dysfunction. The accumulation of SnCs in adipocytes affects their lipid storage and impairs adipogenesis. The inflammatory senescence-associated secretory phenotype (SASP) of SnCs downregulates the antioxidant capacity and mitochondrial function in tissues. Senescent hepatocytes cannot oxidize fatty acids, which leads to lipid deposition and senescence in ß-cells decrease function. These and other adverse effects of SnCs contribute to insulin resistance and type-2 diabetes. The reduction in the SnC burden genetically or pharmacologically improves the complications associated with obesity. The accumulation of SnCs with age and disease accelerates aging. Obesity is a key driver of SnC accumulation, and the complications associated with obesity can be controlled by reducing the SnC burden. Thus, senotherapeutic drugs have the potential to be an effective therapeutic option.

Role of Cellular Senescence in Type II Diabetes.

Cellular senescence is a cell fate that occurs in response to numerous types of stress and can promote tissue repair or drive inflammation and disruption of tissue homeostasis depending on the context. Aging and obesity lead to an increase in the senescent cell burden in multiple organs. Senescent cells release a myriad of senescence-associated secretory phenotype factors that directly mediate pancreatic ß-cell dysfunction, adipose tissue dysfunction, and insulin resistance in peripheral tissues, which promote the onset of type II diabetes mellitus. In addition, hyperglycemia and metabolic changes seen in diabetes promote cellular senescence. Diabetes-induced cellular senescence contributes to various diabetic complications. Thus, type II diabetes is both a cause and consequence of cellular senescence. This review summarizes recent studies on the link between aging, obesity, and diabetes, focusing on the role of cellular senescence in disease processes.

Ferulic acid exerts its antidiabetic effect by modulating insulin-signalling molecules in the liver of high-fat diet and fructose-induced type-2 diabetic adult male rat.

Ferulic acid (FA) is a phenolic phytochemical known for its antidiabetic property The present study is designed to evaluate the mechanism behind its antidiabetic property in high-fat and fructose-induced type 2 diabetic adult male rats. Animals were divided into 5 groups: (i) control, (ii) diabetic control, (iii) diabetic animals treated with FA (50 mg/(kg body weight · day)(-1), orally) for 30 days, (iv) diabetic animals treated with metformin (50 mg/(kg body weight · day)(-1), orally) for 30 days, and (v) control rats treated with FA. FA treatment to diabetic animals restored blood glucose, serum insulin, glucose tolerance, and insulin tolerance to normal range. Hepatic glycogen concentration, activity of glycogen synthase, and glucokinase were significantly decreased, whereas activity of glycogen phosphorylase and enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase)) were increased in diabetic animals and FA restored these to normal levels similar to that of metformin. FA improved the insulin signalling molecules and reduced the negative regulators of insulin signalling. The messenger RNA of gluconeogenic enzyme genes (PEPCK and G6Pase) and the interaction between forkhead transcription factor-O1 and promoters of gluconeogenic enzyme genes (PEPCK and G6Pase) was reduced significantly by ferulic acid. It is concluded from the present study that FA treatment to type 2 diabetic rats improves insulin sensitivity and hepatic glycogenesis but inhibits gluconeogenesis and negative regulators of insulin signalling to maintain normal glucose homeostasis.

Ferulic acid regulates hepatic GLUT2 gene expression in high fat and fructose-induced type-2 diabetic adult male rat.

GLUT2 is a bidirectional glucose transporter present in liver, kidney and pancreas. Studies have shown over-expression of GLUT2 in diabetic conditions. Ferulic acid (FA) is an antidiabetic phenolic phytocompound which is reported to regulate GLUT4 in vitro. The objective of our study is to evaluate the role of FA in the regulation of hepatic GLUT2 expression and the underlying mechanism. Male Wistar rats were divided into 5 groups: control, diabetic (diabetes was induced by giving high fat diet and high fructose water for 60 days), diabetic rats treated with FA (50mg/kg body weight/day, orally for 30 days), diabetic rats treated with metformin (50mg/kg body weight/day, orally for 30 days) and control rats treated with FA (50mg/kg body weight/day orally for 30 days). After 30 days treatment, animals were perfused and liver was dissected out. Glucose uptake and oxidation, expression of GLUT2 and binding of transcription factors - SREBP1c, HNF1α and HNF3ß with GLUT2 gene promoter were studied. Over-expression of GLUT2 in hepatic tissue was found in high fat and fructose- induced type-2 diabetic animals. FA treatment reduced the GLUT2 expression in diabetic animals by impairing the interaction between these transcription factors (SREBP1c, HNF1α and HNF3ß) and GLUT2 gene promoter.

Effect of homeopathic preparations of Syzygium jambolanum and Cephalandra indica on gastrocnemius muscle of high fat and high fructose-induced type-2 diabetic rats.

BACKGROUND: Homeopathy is a holistic method of treatment that uses microdoses of natural substances originating from plants, minerals, or animal parts. Syzygium jambolanum and Cephalandra indica are used in homeopathy for treatment of type-2 diabetes. However, the molecular mechanisms responsible for such effects are not known. METHODS: Homeopathic preparations of S. jambolanum and C. indica in mother tincture, 6c and 30c were used to examine the molecular mechanism of antidiabetic effects in the skeletal muscle of rats with high fat and fructose-induced type-2 diabetes mellitus. After 30 days treatment, fasting blood glucose, serum insulin and insulin signaling molecules in the skeletal muscle (gastrocnemius) were measured. RESULTS: Diabetic rats showed a significant decrease in serum insulin and lipid profile as well as low levels of insulin receptor (IR), v-akt murine thymoma viral oncogene homolog (Akt), p-Akt(ser473) and glucose transporter-4 (GLUT4) protein expression (p < 0.05) with a significant increase in fasting blood glucose level (p < 0.05) compared to the control group. Treatment with homeopathic remedies significantly increased the serum insulin and expression of these proteins (p < 0.05) with a significant decrease in fasting blood glucose (p < 0.05) compared to diabetic rats. CONCLUSIONS: In the present study homeopathic preparations of S. jambolanum and C. indica, including ultramolecular dilutions exhibit antidiabetic effects, improving insulin action through activation of insulin signaling molecules in skeletal muscle of type-2 diabetic rats.

Estradiol favors glucose oxidation in gastrocnemius muscle through modulation of insulin signaling molecules in adult female rats.

INTRODUCTION: Estrogens are steroid compounds that are synthesized in ovary, testis, adrenal cortex and other tissues. Several surveys have shown the potential relationship between estradiol and glucose homeostasis in physiological and pathological states such as the menstrual cycle, gestation, gestational diabetes mellitus and polycystic ovarian syndrome (PCOS). All these states are characterized by variability in estradiol level and some degree of insulin resistance. Skeletal muscle plays a crucial role in maintaining systemic glucose metabolism through activation of assorted signaling molecules. OBJECTIVES: The present study is to evaluate the aftermath of ovariectomy and estradiol replacement on few insulin signaling molecules and GLUT4 protein expression and glucose oxidation in gastrocnemius muscle of adult albino rat. DESIGN: In the present study, Wistar strain albino rats were selected and divided into three groups. Group I: Control (sham-operated). Group II: Ovariectomized and Group III: Estradiol was replaced 7 days after ovariectomy at a dose of 6 µg/kg boxpression of insulin signaling molecules (western blot) and glucose oxidation were assessed. RESULTS: Ovariectomy significantly depleted the expression of insulin signaling molecules and glucose oxidation whereas estradiol replacement improved them. Thus, estradiol helps in maintaining glucose level in ovariectomized rats. Results of this study suggest that estradiol improves the expression of insulin signaling molecules in skeletal muscle and thereby it prevents the onset of insulin resistance as a result of estradiol deficiency.